Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in anim Show more
Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRα in hepatocytes. Liver-specific deletion of LXRα in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRα for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRα increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRα, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRα eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease. Show less
Cytosolic sulfotransferase (SULT2B1b) catalyzes oxysterol sulfation. 5-Cholesten-3β-25-diol-3-sulfate (25HC3S), one product of this reaction, decreases intracellular lipids in vitro by suppressing liv Show more
Cytosolic sulfotransferase (SULT2B1b) catalyzes oxysterol sulfation. 5-Cholesten-3β-25-diol-3-sulfate (25HC3S), one product of this reaction, decreases intracellular lipids in vitro by suppressing liver X receptor/sterol regulatory element binding protein (SREBP)-1c signaling, with regulatory properties opposite to those of its precursor 25-hydroxycholesterol. Upregulation of SULT2B1b may be an effective strategy to treat hyperlipidemia and hepatic steatosis. The objective of the study was to explore the effect and mechanism of oxysterol sulfation by SULT2B1b on lipid metabolism in vivo. C57BL/6 and LDLR(-/-) mice were fed with high-cholesterol diet or high-fat diet for 10 weeks and infected with adenovirus encoding SULT2B1b. SULT2B1b expressions in different tissues were determined by immunohistochemistry and Western blot. Sulfated oxysterols in liver were analyzed by high-pressure liquid chromatography. Serum and hepatic lipid levels were determined by kit reagents and hematoxylin and eosin staining. Gene expressions were determined by real-time reverse transcriptase polymerase chain reaction and Western Blot. Following infection, SULT2B1b was successfully overexpressed in the liver, aorta, and lung tissues, but not in the heart or kidney. SULT2B1b overexpression, combined with administration of 25-hydroxycholesterol, significantly increased the formation of 25HC3S in liver tissue and significantly decreased serum and hepatic lipid levels, including triglycerides, total cholesterol, free cholesterol, and free fatty acids, as compared with controls in both C57BL/6 and LDLR(-/-) mice. Gene expression analysis showed that increases in SULT2B1b expression were accompanied by reduction in key regulators and enzymes involved in lipid metabolism, including liver X receptor α, SREBP-1, SREBP-2, acetyl-CoA carboxylase-1, and fatty acid synthase. These findings support the hypothesis that 25HC3S is an important endogenous regulator of lipid biosynthesis. Show less
The liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, has been shown to regulate the expression of the fatty acid synthase (FAS) gene through direct interaction with the FAS Show more
The liver X receptor alpha (LXRα), a member of the nuclear receptor superfamily, has been shown to regulate the expression of the fatty acid synthase (FAS) gene through direct interaction with the FAS promoter. However, its regulation of gene expression is not completely understood. Histone modifications and chromatin remodeling are closely linked to transcriptional activation of genes. In the present study, we examined the effect of LXRα activation or silencing on histone modifications (i.e., acetylation, methylation, and phosphorylation) across the FAS gene, with the aim to investigate whether LXRα could regulate its target gene expression at the epigenetic level. The addition of LXR agonist T0901317 or ectopic expression of LXRα stimulated the FAS transcription, which was coupled with increased levels of histones H3 and H4 acetylation and H3 phosphorylation and methylation at the LXR response element (LXRE). LXR ligation or overexpression induced distinct histone modification patterns at the distal region 2,272 bp upstream from the transcription start site (TSS) and TSS of the FAS gene. Moreover, RNA interference-mediated downregulation of LXRα impaired the histone acetylation and methylation but not phosphorylation on the FAS gene. In conclusion, we provide evidence that LXRα ligation-mediated transcriptional activation of the FAS gene is associated with LXRα-dependent histone acetylation and methylation rather than phosphorylation on this target gene. Show less
Jinxiu Zhang, Xue Yang, Zheng Wang+4 more · 2012 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
The assembly of supramolecular complexes in multidomain scaffold proteins is crucial for the control of cell polarity. The scaffold protein of protein associated with Lin-7 1 (Pals1) forms a complex w Show more
The assembly of supramolecular complexes in multidomain scaffold proteins is crucial for the control of cell polarity. The scaffold protein of protein associated with Lin-7 1 (Pals1) forms a complex with two other scaffold proteins, Pals-associated tight junction protein (Patj) and mammalian homolog-2 of Lin-7 (Mals2), through its tandem Lin-2 and Lin-7 (L27) domains to regulate apical-basal polarity. Here, we report the crystal structure of a 4-L27 domain-containing heterotrimer derived from the tripartite complex Patj/Pals1/Mals2. The heterotrimer consists of two cognate pairs of heterodimeric L27 domains with similar conformations. Structural analysis and biochemical data further show that the dimers assemble mutually independently. Additionally, such mutually independent assembly of the two heterodimers can be observed in another tripartite complex, Disks large homolog 1 (DLG1)/calcium-calmodulin-dependent serine protein kinase (CASK)/Mals2. Our results reveal a novel mechanism for tandem L27 domain-mediated, supramolecular complex assembly with a mutually independent mode. Show less
PIK3C3/Vps34 is the class III PtdIns3K that is evolutionarily conserved from yeast to mammals. Its central role in mammalian autophagy has been suggested through the use of pharmacological inhibitors Show more
PIK3C3/Vps34 is the class III PtdIns3K that is evolutionarily conserved from yeast to mammals. Its central role in mammalian autophagy has been suggested through the use of pharmacological inhibitors and the study of its binding partners. However, the precise role of PIK3C3 in mammals is not clear. Using mouse strains that allow tissue-specific deletion of PIK3C3, we have described an essential role of PIK3C3 in regulating autophagy, and liver and heart function. Show less
Nadia Jaber, Zhixun Dou, Juei-Suei Chen+8 more · 2012 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elu Show more
A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function. Show less
The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irre Show more
The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3. Show less
Epidermal growth factor (EGF) receptor (EGFR) signal transduction is regulated by endocytosis where many Rab proteins play an important role in the determination of the receptor recycle or degradation Show more
Epidermal growth factor (EGF) receptor (EGFR) signal transduction is regulated by endocytosis where many Rab proteins play an important role in the determination of the receptor recycle or degradation. In an effort to better understand how EGF signaling is regulated, we examined the role of Rab21 in regulation of the degradation and signal transduction of the EGFR. Using a transient expression protocol in HEK293T and HeLa cells, we found that Rab21 enhanced the degradation of EGFR through accelerating its internalization in both EGF-independent and EGF-dependent manners. We further demonstrated that Rab21 interacted with EGFR by immunoprecipitation experiments. Interestingly, we observed that overexpression of Rab21 attenuated EGF-mediated mitogen-activated protein kinase (MAPK) signaling by inducing EGFR degradation. Taken together, these data suggest that Rab21 plays a negative role in the EGF-mediated MAPK signaling pathway. Show less
RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coup Show more
RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs) was examined with four substance dependence diagnoses (alcohol (AD), cocaine (CD), opioid (OD) or marijuana (MjD)] in 1,905 African Americans (AAs: 1,562 cases and 343 controls) and 1,332 European Americans (EAs: 981 cases and 351 controls). Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤P(empirical)≤0.037). The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤P(empirical)≤0.019). This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002) and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185). No RGS20 SNPs were associated with any of the four dependence traits in either population. This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations. Show less
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly rev Show more
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D. Show less
Anorexia nervosa (AN) is a mental illness with high mortality that most commonly afflicts adolescent female individuals. Clinical symptoms include chronic food refusal, weight loss and body image dist Show more
Anorexia nervosa (AN) is a mental illness with high mortality that most commonly afflicts adolescent female individuals. Clinical symptoms include chronic food refusal, weight loss and body image distortions. We carried out a genome-wide association study on 1033 AN cases and 3733 pediatric control subjects, all of whom were of European ancestry and were genotyped on the Illumina HumanHap610 platform (Illumina, San Diego, CA, USA). We confirmed that common single-nucleotide polymorphisms (SNPs) within OPRD1 (rs533123, P=0.0015) confer risk for AN, and obtained suggestive evidence that common SNPs near HTR1D (rs7532266, P=0.04) confer risk for restricting-type AN specifically. However, no SNPs reached genome-wide significance in our data, whereas top association signals were detected near ZNF804B, CSRP2BP, NTNG1, AKAP6 and CDH9. In parallel, we performed genome-wide analysis on copy number variations (CNVs) using the signal intensity data from the SNP arrays. We did not find evidence that AN cases have more CNVs than control subjects, nor do they have over-representation of rare or large CNVs. However, we identified several regions with rare CNVs that were only observed in AN cases, including a recurrent 13q12 deletion (1.5 Mb) disrupting SCAS in two cases, and CNVs disrupting the CNTN6/CNTN4 region in several AN cases. In conclusion, our study suggests that both common SNPs and rare CNVs may confer genetic risk to AN. These results point to intriguing genes that await further validation in independent cohorts for confirmatory roles in AN. Show less
The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins Show more
The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates. Show less
To analyze serum proteomics differences between normal and foot and mouth disease virus (FMDV)-infected piglets, an analytical method based on liquid chromatography with tandem mass spectrometry (LC-M Show more
To analyze serum proteomics differences between normal and foot and mouth disease virus (FMDV)-infected piglets, an analytical method based on liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used. Samples of venous blood were collected before and after FMDV infection and high abundance serum albumin was removed using a commercial kit. After trypsin digestion, serum samples were processed with LC-MS/MS. Proteins were identified by peptide mass fingerprinting. We found that apolipoprotein A-IV precursor, haptoglobin and probable chemoreceptor glutamine deamidase cheD appeared after FMDV infection in the same piglet. This is believed to be the first time that serum proteomics analysis by LC-MS/MS after FMDV infection has been performed, and our results may provide further information about biomarkers for early diagnosis of FMD in piglets. Show less
Endometrial carcinoma is one of the most common gynecological malignancies in women. The diagnosis of the disease at early or premalignant stages is crucial for the patient's prognosis. To date, diagn Show more
Endometrial carcinoma is one of the most common gynecological malignancies in women. The diagnosis of the disease at early or premalignant stages is crucial for the patient's prognosis. To date, diagnosis and follow-up of endometrial carcinoma and hyperplasia require invasive procedures. Therefore, there is considerable demand for the identification of biomarkers to allow non-invasive detection of these conditions. In this study, we performed a quantitative proteomics analysis on serum samples from simple endometrial hyperplasia, complex endometrial hyperplasia, atypical endometrial hyperplasia, and endometrial carcinoma patients, as well as healthy women. Serum samples were first depleted of high-abundance proteins, labeled with isobaric tags (iTRAQ), and then analyzed via two-dimensional liquid chromatography and tandem mass spectrometry. Protein identification and quantitation information were acquired by comparing the mass spectrometry data against the International Protein Index Database using ProteinPilot software. Bioinformatics annotation of identified proteins was performed by searching against the PANTHER database. In total, 74 proteins were identified and quantified in serum samples from endometrial lesion patients and healthy women. Using a 1.6-fold change as the benchmark, 12 proteins showed significantly altered expression levels in at least one disease group compared with healthy women. Among them, 7 proteins were found, for the first time, to be differentially expressed in atypical endometrial hyperplasia. These proteins are orosomucoid 1, haptoglobin, SERPINC 1, alpha-1-antichymotrypsin, apolipoprotein A-IV, inter-alpha-trypsin inhibitor heavy chain H4, and histidine-rich glycoprotein. The differentially expressed proteins we discovered in this study may serve as biomarkers in the diagnosis and follow-up of endometrial hyperplasia and endometrial carcinoma. Show less
The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been sug Show more
The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment. Show less
The relation has not been reported consistently between the polymorphisms in the gene of apolipoprotein A5 (APO A5) and coronary artery disease (CAD). To clarify the discrepancy, we conducted a compre Show more
The relation has not been reported consistently between the polymorphisms in the gene of apolipoprotein A5 (APO A5) and coronary artery disease (CAD). To clarify the discrepancy, we conducted a comprehensive search of PubMed and EMBASE for all available casecontrol studies to explore the association between two APO A5 polymorphisms and CAD. Two reviewers independently selected studies. Statistical analyses were carried out using the STATA software package v 10.0. Thirteen studies investigated the association between the APO A5 -1131T>C polymorphism and risk of CAD were selected in this meta-analysis with 5,050 cases and 7,272 controls. For the S19W APO A5 gene polymorphism, 5 studies were included with 2,196 cases and 3,933 controls. We observed a significant statistical association between Apo A5 -1131T>C polymorphism and CAD (recessive genetic model: OR = 1.73, 95% CI = 1.37-2.19; dominant genetic model: OR = 1.42, 95% CI = 1.25-1.61; allelic contrast: OR = 1.31, 95% CI = 1.22-1.39, respectively). After restricting our analysis to Chinese individuals, we found that the association was stronger. We also observed strong association between the APO A5 S19>W polymorphism and risk of CAD under a recessive genetic model. This meta-analysis reveals that the minor allele of the -1131T>C polymorphism in the promoter of APO A5 gene significantly increases the susceptibility to CAD. This effect is more pronounced in Chinese subjects. Show less
Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statist Show more
Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease. Show less
Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of Apo Show more
Little is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5-1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels. A total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05-0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between -1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The -1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the -1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05-0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05-0.01). The differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption. Show less
OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and car Show more
OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants. Show less
Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of ischemic stroke. Recently, t Show more
Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of ischemic stroke. Recently, the -1131T>C polymorphism in apolipoprotein A5 (APOA5) gene has been reported to be associated with ischemic stroke in different racial groups, but no data is available currently in Han Chinese. Our study is to investigate the association between the APOA5 gene polymorphism -1131T>C and the susceptibility to ischemic stroke in Han Chinese. 310 controls and 342 patients with classified ischemic stroke were performed to detect the -1131T>C alleles genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in independent case-control study. TG levels of subjects carrying -1131C allele were elevated compared to the subjects with -1131T allele in all ischemic stroke subgroups and in controls. The serum TC, LDL-C and HDL-C levels did not differ between subjects with T or C alleles in each group. The overall distribution of APOA5 -1131T>C genotype among stroke patients and controls was significantly different (P<0.01). Frequencies of CC homozygote and C allele were significantly higher in all stroke subgroups than those in control group. After adjustment for conventional risk factors, logistic regression analysis showed that C allele carrier (CC+CT) of -1131T>C was an independent risk factor for all stroke subgroups (P<0.05). APOA5 gene -1131T>C polymorphism is independently associated with the development of ischemic stroke in Chinese Han population, and CC homozygote may have a promoting effect on ischemic stroke. Show less
Apolipoprotein (APO) A5 gene polymorphisms have been associated with increased plasma triglyceride (TG), but the results are inconsistent. The present study was undertaken to detect the APOA5 gene pol Show more
Apolipoprotein (APO) A5 gene polymorphisms have been associated with increased plasma triglyceride (TG), but the results are inconsistent. The present study was undertaken to detect the APOA5 gene polymorphisms and their associations with lipid profiles in the Guangxi Hei Yi Zhuang and Han populations. Genotyping of the APOA5 -1131T>C, c.553G>T and c.457G>A was performed in 490 subjects of Hei Yi Zhuang and 540 participants of Han Chinese aged 15-89 years. The -1131C allele frequency was higher in high total cholesterol (TC) than in normal TC subgroups in both the ethnic groups (P<0.05). The c.553T allele frequency was higher in high TG than in normal TG subgroups (P<0.01), in high APOB than in normal APOB subgroups in Hei Yi Zhuang (P<0.05), or in females than in males in Han (P<0.01). The c.457A allele frequency in Han was higher in high TG than in normal TG subgroups, in low APOA1 than in normal APOA1 subgroups, in males than in females, or in normal APOB than in high APOB subgroups (P<0.05-0.01). The levels of TC, low-density lipoprotein cholesterol and APOB in Hei Yi Zhuang were correlated with -1131T>C genotype or allele, and the levels of TG were associated with c.553G>T genotype (P<0.05). The levels of TG, APOA1 and APOB in Han were correlated with c.457G>A genotype or allele, and the levels of TC were associated with -1131T>C allele (P<0.05). The differences in the lipid profiles between the two ethnic groups might partly result from different APOA5 gene-environmental interactions. Show less
Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single Show more
Nonalcoholic fatty liver disease (NAFLD) and insulin resistance have recently been found to be associated with increased plasma concentrations of apolipoprotein CIII (APOC3) in humans carrying single nucleotide polymorphisms within the insulin response element of the APOC3 gene. To examine whether increased expression of APOC3 would predispose mice to NAFLD and hepatic insulin resistance, human APOC3 overexpressing (ApoC3Tg) mice were metabolically phenotyped following either a regular chow or high-fat diet (HFD). After HFD feeding, ApoC3Tg mice had increased hepatic triglyceride accumulation, which was associated with cellular ballooning and inflammatory changes. ApoC3Tg mice also manifested severe hepatic insulin resistance assessed by a hyperinsulinemic-euglycemic clamp, which could mostly be attributed to increased hepatic diacylglycerol content, protein kinase C-ϵ activation, and decreased insulin-stimulated Akt2 activity. Increased hepatic triglyceride content in the HFD-fed ApoC3Tg mice could be attributed to a ≈ 70% increase in hepatic triglyceride uptake and ≈ 50% reduction hepatic triglyceride secretion. These data demonstrate that increase plasma APOC3 concentrations predispose mice to diet-induced NAFLD and hepatic insulin resistance. Show less
Yong Yan Song, Ren Rong Gong, Zhen Zhang+4 more · 2011 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas · added 2026-04-24
Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo Show more
Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 ± 1.80 years) were given a washout diet of 54% carbohydrate for 7 days, followed by a high-CHO diet of 70% carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 ± 1.00 vs 2.36 ± 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 ± 0.74 vs 2.09 ± 0.55, P = 0.000; female S2 carriers: 2.68 ± 0.36 vs 2.24 ± 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 ± 0.41 vs 2.09 ± 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 ± 0.71 vs 1.06 ± 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 ± 0.61 vs 1.01 ± 0.29, P = 0.005; female S2 carriers: 1.18 ± 0.33 vs 1.00 ± 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 ± 0.35 vs 1.04 ± 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 ± 0.46 vs 1.63 ± 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has favorable effects on the TC/HDL-C and LDL-C/HDL-C ratios regardless of gender and of genotype of the APOC3 SstI polymorphism. Somehow, it enhanced the adverse effect of the S2 allele on the TG/HDL-C ratio only in females. Show less
Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Barde Show more
Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling. Show less
The NF-κB and IL6/STAT3 pathways are major participants in tumor-promoting inflammation. C1qTNF related protein (CTRP) is a family with multiple physiological functions, but their involvement in tumor Show more
The NF-κB and IL6/STAT3 pathways are major participants in tumor-promoting inflammation. C1qTNF related protein (CTRP) is a family with multiple physiological functions, but their involvement in tumor-promoting inflammation has received little attention. For the first time, we have identified CTRP4 as a novel secretary protein by N-terminal sequencing. Moreover, recombinant CTRP4 can effectively induce the activation of both NF-κB and IL6/STAT3 signaling pathways in the pattern similar to that of classical cytokine. By western blot analysis, we detected the upregulation of CTRP4 in response to IL6. Importantly, functional research revealed that CTRP4 could promote tumor cell survival and tumor resistance against apoptosis induced by chemotherapeutics. These results strongly suggest that CTRP4 is a novel tumor-promoting inflammatory regulator. Our findings might provide a meaningful indication for cancer research. Show less
The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and t Show more
The innate immune system detects viral infection predominantly by sensing viral nucleic acids. We report the identification of a viral sensor, consisting of RNA helicases DDX1, DDX21, and DHX36, and the adaptor molecule TRIF, by isolation and sequencing of poly I:C-binding proteins in myeloid dendritic cells (mDCs). Knockdown of each helicase or TRIF by shRNA blocked the ability of mDCs to mount type I interferon (IFN) and cytokine responses to poly I:C, influenza A virus, and reovirus. Although DDX1 bound poly I:C via its Helicase A domain, DHX36 and DDX21 bound the TIR domain of TRIF via their HA2-DUF and PRK domains, respectively. This sensor was localized within the cytosol, independent of the endosomes. Thus, the DDX1-DDX21-DHX36 complex represents a dsRNA sensor that uses the TRIF pathway to activate type I IFN responses in the cytosol of mDCs. Show less
Recent genome-wide association (GWA) studies have identified a number of novel genetic determinants of blood lipid concentrations in Europeans. However, it is still unclear whether these loci identifi Show more
Recent genome-wide association (GWA) studies have identified a number of novel genetic determinants of blood lipid concentrations in Europeans. However, it is still unclear whether these loci identified in the Caucasian GWA studies also exert the same effect on lipid concentrations in the Chinese population. We conducted a replication study assessing associations between SNPs at 15 loci and blood lipid and lipoprotein concentrations in two Chinese cohorts, comprising 2533 and 2105 individuals respectively. SNPs in APO(A1/C3/A4/A5), TIMD4-HAVCR1, DOCK7, TRIB1, ABCA1, and TOMM40-APOE showed strong associations with at least one lipids trait, and rs174546 in FADS1/2/3 showed modest association with triglyceride in the Chinese population. We successfully replicated 7 loci associated plasma lipid concentrations in the Chinese population. Our study confirmed the implication of APO(A1/C3/A4/A5), TOMM40-APOE, ABCA1, DOCK7, TIMD4-HAVCR1, TRIB1 and FADS1/2 in plasma lipid and lipoprotein concentrations in Chinese population. Show less
Yuan-Yuan Zhang, Jia-Wei Wu, Zhi-Xin Wang · 2011 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
MAPK phosphatase 3 (MKP3) is highly specific for ERK1/2 inactivation via dephosphorylation of both phosphotyrosine and phosphothreonine critical for enzymatic activation. Here, we show that MKP3 is ab Show more
MAPK phosphatase 3 (MKP3) is highly specific for ERK1/2 inactivation via dephosphorylation of both phosphotyrosine and phosphothreonine critical for enzymatic activation. Here, we show that MKP3 is able to effectively dephosphorylate the phosphotyrosine, but not phosphothreonine, in the activation loop of p38α in vitro and in intact cells. The catalytic constant of the MKP3 reaction for p38α is comparable with that for ERK2. Remarkably, MKP3, ERK2, and phosphorylated p38α can form a stable ternary complex in solution, and the phosphatase activity of MKP3 toward p38α substrate is allosterically regulated by ERK2-MKP3 interaction. This suggests that MKP3 not only controls the activities of ERK2 and p38α but also mediates cross-talk between these two MAPK pathways. The crystal structure of bisphosphorylated p38α has been determined at 2.1 Å resolution. Comparisons between the phosphorylated MAPK structures reveal the molecular basis of MKP3 substrate specificity. Show less
The study was aimed to provide insights into genes governing the early stages of cell proliferation ability alteration and mechano-response in human periodontal ligament cells (PDLCs) induced by short Show more
The study was aimed to provide insights into genes governing the early stages of cell proliferation ability alteration and mechano-response in human periodontal ligament cells (PDLCs) induced by short-term cyclic tensile stress. Primary human PDLCs were subjected to cyclic tensile stress (0.5 Hz, 5000 μstrain) for 2h through a four-point bending strain system. After that, cell viability and proliferation ability were examined by MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry. Furthermore, the gene expression profile was investigated by microarray analysis, and the reliability of which was verified by quantitative RT-PCR. MTT assay and flow cytometry demonstrated that mechanical stress inhibited functional expression and slowed down proliferation of cells. Microarray analysis showed that 110 genes related to cyclic tensile stress were identified in total. Amongst them, ninety-seven were up-regulated, whilst 13 were down-regulated. Eleven genes (KLF10, ETS1, CKS2, DUSP6, KIF23, MAPK6, SERTAD1, IRF1, MAPRE1, CCNB1 and BCAR3) regarding cell cycle arrest were identified. Seven up-regulated genes (PTGS2, KLF10, CDC42EP2, BHLHB2, SPRY2, IER3 and CCL2) were verified by quantitative RT-PCR, which supported the microarray results. Cell cycle arrest and the slow-down proliferation can benefit PDLCs to have more time to respond to mechanical stimuli, and the differential gene expression reflects the behaviour of cells. Those genes in response to cyclic tensile stress were identified in human PDLCs, some of which are related with the mechano-induced cell cycle arrest. Show less
Multiple osteochondromas (MO), an inherited autosomal dominant disorder, is characterized by the presence of multiple exostoses on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes w Show more
Multiple osteochondromas (MO), an inherited autosomal dominant disorder, is characterized by the presence of multiple exostoses on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes which encode glycosyltransferases implicated in heparin sulfate biosynthesis. In this study, efforts were made to identify the underlying disease-causing mutations in patients from two MO families in China. Two novel EXT1 gene mutations were identified and no mutation was found in EXT2 gene. The mutation c.497T > A in exon 1 of the EXT1 gene was cosegregated with the disease phenotype in family 1 and formed a stop codon at amino acid site 166. The fetus of the proband was diagnosed negative. In family 2, the mutation c.1430-1431delCC in exon 6 of the EXT1 gene would cause frameshift and introduce a premature stop codon after the reading frame being open for 42 amino acids. The fetus of this family inherited this mutation from the father. Mutation analysis of two MO families in this study demonstrates its further application in MO genetic counseling and prenatal diagnosis. Show less